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1.  Reproducibility of exhaled nitric oxide measurements in overweight and obese adults 
BMC Research Notes  2014;7(1):775.
Exhaled nitric oxide is a noninvasive measure of airway inflammation that can be detected by a handheld device. Obesity may influence the reproducibility of exhaled nitric oxide measurements, by - for instance – decreased expiratory reserve volume.
We analyzed triple exhaled nitric oxide measurements from 553 participants (aged 45 to 65 years with a body mass index ≥27 kg/m2) of the Netherlands Epidemiology of Obesity Study. The interclass correlation coefficient (single measurement reliability) was 0.965 (95% CI: 0.960, 0.970).
We conclude that for assessment of exhaled nitric oxide in large cohorts of overweight and obese adults a single measurement suffices.
PMCID: PMC4237750  PMID: 25366981
Reproducibility; Exhaled nitric oxide; Obesity
2.  Adiposity and hand osteoarthritis: the Netherlands Epidemiology of Obesity study 
Obesity, usually characterized by the body mass index (BMI), is a risk factor for hand osteoarthritis (OA). We investigated whether adipose tissue and abdominal fat distribution are associated with hand OA.
The Netherlands Epidemiology of Obesity (NEO) study is a population-based cohort aged 45 to 65 years, including 5315 participants (53% women, median BMI 29.9 kg/m2). Fat percentage and fat mass (FM) (kg) were estimated using bioelectrical impedance analysis. The waist-to-hip ratio (WHR) was calculated. In 1721 participants, visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) (cm2) were assessed using abdominal MR imaging. Hand OA was defined according to the ACR criteria.
Odds ratios (OR) with 95% confidence intervals (CI) were calculated for the association of fat percentage, FM, WHR, VAT and SAT with hand OA using logistic regression analyses per standard deviation, stratified by sex and adjusted for age.
Hand OA was present in 8% of men and 20% of women. Fat percentage was associated with hand OA in men (OR 1.34 (95% CI 1.11 to 1.61)) and women (OR 1.26 (1.05 to 1.51)), as was FM. WHR was associated with hand OA in men (OR 1.45 (1.13 to 1.85)), and to a lesser extent in women (OR 1.17 (1.00 to 1.36)). Subgroup analysis revealed that VAT was associated with hand OA in men (OR1.33 (1.01 to 1.75)). This association increased after additional adjustment for FM (OR 1.51 (1.13 to 2.03)).
Fat percentage, FM and WHR were associated with hand OA. VAT was associated with hand OA in men, suggesting involvement of visceral fat in hand OA.
PMCID: PMC3978723  PMID: 24447395
4.  Severe Obstetric Brachial Plexus Palsies Can Be Identified at One Month of Age 
PLoS ONE  2011;6(10):e26193.
To establish whether severe obstetric brachial plexus palsy (OBPP) can be identified reliably at or before three months of age.
Severe OBPP was defined as neurotmesis or avulsion of spinal nerves C5 and C6 irrespective of additional C7-T1 lesions, assessed during surgery and confirmed by histopathological examination. We first prospectively studied a derivation group of 48 infants with OBPP with a minimal follow-up of two years. Ten dichotomous items concerning active clinical joint movement and needle electromyography of the deltoid, biceps and triceps muscles were gathered at one week, one month and three months of age. Predictors for a severe lesion were identified using a two-step forward logistic regression analysis. The results were validated in two independent cohorts of OBPP infants of 60 and 13 infants.
Prediction of severe OBPP at one month of age was better than at one week and at three months. The presence of elbow extension, elbow flexion and of motor unit potentials in the biceps muscle correctly predicted whether lesions were mild or severe in 93.6% of infants in the derivation group (sensitivity 1.0, specificity 0.88), in 88.3% in the first validation group (sensitivity 0.97, specificity 0.76) and in 84.6% in the second group (sensitivity of 1.0, specificity 0.66).
Infants with OBPP with severe lesions can be identified at one month of age by testing elbow extension, elbow flexion and recording motor unit potentials (MUPs) in the biceps muscle. The decision rule implies that children without active elbow extension at one month should be referred to a specialized center, while children with active elbow extension as well as active flexion should not. When there is active elbow extension, but no active elbow flexion an EMG is needed; absence of MUPs in the biceps muscle is an indication for referral.
PMCID: PMC3197138  PMID: 22043309
5.  Asymmetric Dimethylarginine (ADMA) Levels Display a Morning Peak in Patients with Acute Myocardial Infarction 
Disease markers  2011;30(5):245-252.
High Asymmetric Dimethylarginine (ADMA) levels are associated with increased platelet activity, elevated blood pressure, vasoconstriction and impaired vascular relaxation. We hypothesized that the myocardial infarction morning peak of occurrence is closely related to a morning peak of ADMA levels. We performed a cross-sectional study among patients with documented myocardial infarction who had been enrolled in the prospective MISSION! Intervention Study. In total, serum ADMA levels were measured in their acute setting of myocardial infarction in 120 patients. The frequency of myocardial infarction onset of symptoms and emergency coronary catheterization and the ADMA levels displayed a similar daily pattern with a morning peak between 06:00–11:59 h. The absolute ADMA levels peak was between 06:00–07:59 h with a median (interquartile range) peak value of 1.01 (0.84–1.21) μmol/L for the n = 9 patients vs. 0.75 (0.61–0.89) μmol/L for the remaining 111 patients admitted throughout the rest of the 24-hour interval (p = 0.003 for between groups comparison). The amplitude (95% confidence interval) of the circadian variation of ADMA levels was 0.08 μmol/L (0.004–0.16) with p = 0.042 for statistic model significance.
In conclusion, ADMA levels display a 24-hour variation with a significant morning peak in patients with acute myocardial infarction. These findings may relate ADMA levels to the acute onset of thrombotic cardiovascular events.
PMCID: PMC3825079  PMID: 21734344
Asymmetric dimethylarginine; myocardial infarction; circadian rhythm; platelets; thrombosis
6.  Association of a Single-Nucleotide Polymorphism in CD40 With the Rate of Joint Destruction in Rheumatoid Arthritis 
Arthritis and rheumatism  2009;60(8):2242-2247.
The severity of joint destruction in rheumatoid arthritis (RA) is highly variable from patient to patient and is influenced by genetic factors. Genome-wide association studies have enormously boosted the field of the genetics of RA susceptibility, but risk loci for RA severity remain poorly defined. A recent meta-analysis of genome-wide association studies identified 6 genetic regions for susceptibility to autoantibody-positive RA: CD40, KIF5A/PIP4K2C, CDK6, CCL21, PRKCQ, and MMEL1/TNFRSF14. The purpose of this study was to investigate whether these newly described genetic regions are associated with the rate of joint destruction.
RA patients enrolled in the Leiden Early Arthritis Clinic were studied (n = 563). Yearly radiographs were scored using the Sharp/van der Heijde method (median followup 5 years; maximum followup 9 years). The rate of joint destruction between genotype groups was compared using a linear mixed model, correcting for age, sex, and treatment strategies. A total of 393 anti–citrullinated protein antibody (ACPA)–positive RA patients from the North American Rheumatoid Arthritis Consortium (NARAC) who had radiographic data available were used for the replication study.
The TT and CC/CG genotypes of 2 single-nucleotide polymorphisms, rs4810485 (CD40) and rs42041 (CDK6), respectively, were associated with a higher rate of joint destruction in ACPA-positive RA patients (P = 0.003 and P = 0.012, respectively), with rs4810485 being significant after Bonferroni correction for multiple testing. The association of the CD40 minor allele with the rate of radiographic progression was replicated in the NARAC cohort (P = 0.021).
A polymorphism in the CD40 locus is associated with the rate of joint destruction in patients with ACPA-positive RA. Our findings provide one of the first non–HLA-related genetic severity factors that has been replicated.
PMCID: PMC3121053  PMID: 19644859
7.  The analysis of longitudinal quality of life measures with informative drop-out: a pattern mixture approach 
Quality of Life Research  2009;19(1):137-148.
The analysis of longitudinal health-related quality of life measures (HRQOL) can be seriously hampered due to informative drop-out. Random effects models assume Missing At Random and do not take into account informative drop-out. We therefore aim to correct the bias due to informative drop-out.
Analyses of data from a trial comparing standard-dose and high-dose chemotherapy for patients with breast cancer with respect to long-term impact on HRQOL will serve as illustration. The subscale Physical Function (PF) of the SF36 will be used. A pattern mixture approach is proposed to account for informative drop-out. Patterns are defined based on events related to HRQOL, such as death and relapse. The results of this pattern mixture approach are compared to the results of the commonly used random effects model.
The findings of the pattern mixture approach are well interpretable, and different courses over time in different patterns are distinguished. In terms of estimated differences between standard dose and high dose, the results of both approaches are slightly different, but have no consequences for the clinical evaluation of both doses.
Under the assumption that drop-out is at random within the patterns, the pattern mixture approach adjusts the estimates to a certain degree. This approach accounts in a relatively simple way for informative drop-out.
PMCID: PMC2804788  PMID: 20041307
Health-related quality of life; Informative drop-out; Longitudinal studies; Missing values; Pattern mixture model
8.  Association of the 6q23 region with the rate of joint destruction in rheumatoid arthritis 
Annals of the Rheumatic Diseases  2009;69(3):567-570.
Two novel genetic polymorphisms on chromosome 6q23 are associated with susceptibility to rheumatoid arthritis (RA). Both polymorphisms (rs6920220 and rs10499194) reside in a region close to the gene encoding tumour necrosis factor α-induced protein 3 (TNFAIP3). TNFAIP3 is a negative regulator of NF-κB and is involved in inhibiting TNF-receptor-mediated signalling effects. Interestingly, the initial associations were detected in patients with longstanding RA. However, no association was found for rs10499194 in a Swedish cohort with early arthritis. This might be caused by over-representation of patients with severe disease in cohorts with longstanding RA.
To analyse the effect of the 6q23 region on the rate of joint destruction.
Five single nucleotide polymorphisms in 6q23 were genotyped in 324 Dutch patients with early RA. Genotypes were correlated with progression of radiographic joint damage for a follow-up time of 5 years.
Two polymorphisms (rs675520 and rs9376293) were associated with severity of radiographic joint damage in patients positive for anti-citrullinated protein/peptide antibodies (ACPA). Importantly, the effects were present after correction for confounding factors such as secular trends in treatment.
These data associate the 6q23 region with the rate of joint destruction in ACPA+ RA.
PMCID: PMC2927680  PMID: 19366996
9.  Use of Framingham risk score and new biomarkers to predict cardiovascular mortality in older people: population based observational cohort study 
Objectives To investigate the performance of classic risk factors, and of some new biomarkers, in predicting cardiovascular mortality in very old people from the general population with no history of cardiovascular disease.
Design The Leiden 85-plus Study (1997-2004) is an observational prospective cohort study with 5 years of follow-up.
Setting General population of the city of Leiden, the Netherlands.
Participants Population based sample of participants aged 85 years (215 women and 87 men) with no history of cardiovascular disease; no other exclusion criteria.
Main measurements Cause specific mortality was registered during follow-up. All classic risk factors included in the Framingham risk score (sex, systolic blood pressure, total and high density lipoprotein cholesterol, diabetes mellitus, smoking and electrocardiogram based left ventricular hypertrophy), as well as plasma concentrations of the new biomarkers homocysteine, folic acid, C reactive protein, and interleukin 6, were assessed at baseline.
Results During follow-up, 108 of the 302 participants died; 32% (35/108) of deaths were from cardiovascular causes. Classic risk factors did not predict cardiovascular mortality when used in the Framingham risk score (area under receiver operating characteristic curve 0.53, 95% confidence interval 0.42 to 0.63) or in a newly calibrated model (0.53, 0.43 to 0.64). Of the new biomarkers studied, homocysteine had most predictive power (0.65, 0.55 to 0.75). Entering any additional risk factor or combination of factors into the homocysteine prediction model did not increase its discriminative power.
Conclusions In very old people from the general population with no history of cardiovascular disease, concentrations of homocysteine alone can accurately identify those at high risk of cardiovascular mortality, whereas classic risk factors included in the Framingham risk score do not. These preliminary findings warrant validation in a separate cohort.
PMCID: PMC2615548  PMID: 19131384
10.  Sick leave and work disability in patients with early arthritis 
Clinical Rheumatology  2007;27(1):11-19.
We studied the occurrence of sick leave and work disability, the presence of workplace adaptations and the usage of professional guidance related to working problems in patients with early arthritis. Inclusion criteria were arthritis symptoms of less than 2 years duration and a paid job at the time of diagnosis. Assessments were done in connection with an early arthritis clinic (EAC) at entry into the cohort and 12 months thereafter by means of a questionnaire comprising questions on sick leave (absenteeism from work reported to the employer), work disability (receiving a full or partial work disability pension), unemployment, work adaptations and professional guidance related to working problems. Fifty-seven of the 69 participants (83%) had an arthritis symptom duration of <6 months. The number of patients with sick leave due to arthritis in the past 12 months decreased from 28 (41%) at study entry to 18 (26%) after 12 months of follow-up. The number of patients receiving a work disability pension increased from 5 (7%) at study entry to 13 (19%) after 12 months of follow-up (10 partial and 3 full). Sick leave in the 12 months before study entry appeared to be the most important predictor of the institution or increase in a work disability pension (odds ratio, 16.1; 95%CI, 1.8–142.8). Between study entry and follow-up, the number of patients with workplace adaptations increased from 20 (29%) to 28 (42%), whereas the number of patients receiving vocational guidance decreased from 48 (70%) to 36 (52%). In patients with early arthritis and a paid job, arthritis-related sick leave was common and occurred in part before patients entered the EAC and a diagnosis was made. About 20% of the patients became permanently work disabled, with partial work disability being more common than full work disability. Considerable proportions of patients received workplace adaptations and professional guidance with working problems.
PMCID: PMC2092406  PMID: 17492248
Arthritis; Occupational health; Sick leave; Vocational rehabilitation; Work disability
11.  Induction of labour versus expectant monitoring in women with pregnancy induced hypertension or mild preeclampsia at term: the HYPITAT trial 
Hypertensive disorders, i.e. pregnancy induced hypertension and preeclampsia, complicate 10 to15% of all pregnancies at term and are a major cause of maternal and perinatal morbidity and mortality. The only causal treatment is delivery. In case of preterm pregnancies conservative management is advocated if the risks for mother and child remain acceptable. In contrast, there is no consensus on how to manage mild hypertensive disease in pregnancies at term. Induction of labour might prevent maternal and neonatal complications at the expense of increased instrumental vaginal delivery rates and caesarean section rates.
Women with a pregnancy complicated by pregnancy induced hypertension or mild preeclampsia at a gestational age between 36+0 and 41+0 weeks will be asked to participate in a multi-centre randomised controlled trial. Women will be randomised to either induction of labour or expectant management for spontaneous delivery. The primary outcome of this study is severe maternal morbidity, which can be complicated by maternal mortality in rare cases. Secondary outcome measures are neonatal mortality and morbidity, caesarean and vaginal instrumental delivery rates, maternal quality of life and costs. Analysis will be by intention to treat. In total, 720 pregnant women have to be randomised to show a reduction in severe maternal complications of hypertensive disease from 12 to 6%.
This trial will provide evidence as to whether or not induction of labour in women with pregnancy induced hypertension or mild preeclampsia (nearly) at term is an effective treatment to prevent severe maternal complications.
Trial Registration
The protocol is registered in the clinical trial register number ISRCTN08132825.
PMCID: PMC1950708  PMID: 17662114
12.  Association between microscopic brain damage as indicated by magnetization transfer imaging and anticardiolipin antibodies in neuropsychiatric lupus 
The pathogenetic role of anticardiolipin antibodies (aCLs) in patients with neuropsychiatric systemic lupus erythematosus (NPSLE) without cerebral infarcts remains elusive. Magnetization transfer imaging (MTI) has proved to be a sensitive tool for detecting diffuse microscopic brain damage in NPSLE patients. In this study we examined the correlation between grey and white matter magnetization transfer ratio (MTR) parameters and the presence of IgM and IgG aCLs and lupus anticoagulant in 18 patients with systemic lupus erythematosus and a history of NPSLE but without cerebral infarcts on conventional magnetic resonance imaging. Lower grey matter mean MTR (P < 0.05), white matter mean MTR (P < 0.05), white matter peak location (P < 0.05) and grey matter peak location (trend toward statistical significance) were observed in IgM aCL-positive patients than in IgM aCL-negative patients. No significant differences were found in MTR histogram parameters with respect to IgG aCL and lupus anticoagulant status, nor with respect to anti-dsDNA or anti-ENA (extractable nuclear antigen) status. This is the first report of an association between the presence of aCLs and cerebral damage in grey and white matter in NPSLE. Our findings suggest that aCLs are associated with diffuse brain involvement in NPSLE patients.
PMCID: PMC1526597  PMID: 16469116
13.  Pathogens involved in lower respiratory tract infections in general practice. 
BACKGROUND: There are few investigations into the aetiology of lower respiratory tract infections (LRTIs) in general practice. AIM: To describe the aetiology of LRTI among adult patients in general practice in The Netherlands. DESIGN OF STUDY: Prospective observational study. SETTING: General practices in the Leiden region, The Netherlands. METHOD: Adult patients with a defined LRTI were included. Standard medical history and physical examination were performed. Sputum, blood and throat swabs were collected for diagnostic tests. Aetiological diagnosis, categorised as definite or possible, was based on the results of bacterial and viral cultures, serological techniques, and on polymerase chain reaction. Proportions of pathogens causing LRTI were assessed in relation to chest X-ray findings. RESULTS: A bacterial cause was established in 43 (30%), and a viral cause in 57 (39%) of the 145 patients with a LRTI. Influenza virus A was the most frequently diagnosed microorganism, followed by Haemophilus influenzae, and Mycoplasma pneumoniae. Streptococcus pneumoniae was found in 6% of the patients. CONCLUSIONS: Pathogens were found in two-thirds of the patients. In half of these patients there was a viral cause. Influenza virus A was the most frequently found pathogen. The treatment with antibiotics of at least one-third of the patients with LRTI was superfluous. This observation should result in changes in the prescription of antibiotics in LRTI.
PMCID: PMC1314772  PMID: 14965401
14.  A diagnostic rule for the aetiology of lower respiratory tract infections as guidance for antimicrobial treatment. 
BACKGROUND: The majority of patients with lower respiratory tract infections (LRTIs) are treated with antibiotics; some of them are unnecessary because of a viral cause. Information on prediction of the aetiology, especially in a general practice setting, is missing. AIM: To differentiate between viral and bacterial LRTI on simple clinical criteria, easily obtained at the bedside. DESIGN OF STUDY: Prospective observational study. SETTING: General practices in the Leiden region of The Netherlands. METHOD: Adult patients with LRTI were included. Standard medical history and physical examination were performed. Sputum, blood and throat swabs were collected for diagnostic tests. According to microbiological findings, patients were classified as bacterial, viral, dual infection and unknown cause. In a logistic regression model independent predictors were determined. Scoring systems were developed. The accuracies of the diagnostic rules were tested by using receiver operating characteristic (ROC) curves. RESULTS: One-hundred and forty-five patients were classified as having bacterial (n = 35), viral (n = 49), or dual infection (n = 8), or infection of unknown cause (n = 53), respectively. Independent predictors for bacterial infection were fever (odds ratio [OR] = 8.0; 95% confidence interval [CI] = 0.9 to 71.0), headache (OR = 4.3; 95% CI = 1.0 to 19.1) cervical painful lymph nodes (OR = 8.7; 95% CI = 1.1 to 68.0), diarrhoea (OR = 0.3; 95% CI = 0.1 to 1.0) and rhinitis (OR = 0.3; 95% CI = 0.1 to 0.9). As an additional independent predictor, an infiltrate on chest X-ray (OR = 5.0; 95% CI = 1.2 to 20.5) was found. The diagnostic rules developed from these variables classified the aetiology of LRTI with a ROC curve area of 0.79 (clinical score), 0.77 (simplified score) and 0.83 (extended score). CONCLUSIONS: A diagnostic rule was developed, based on information that is easy to obtain at the bedside, to predict a bacterial infection. This diagnostic rule may be a tool for general practitioners in their management of patients with LRTI.
PMCID: PMC1314773  PMID: 14965402
15.  Effect of providing free glasses on children’s educational outcomes in China: cluster randomized controlled trial 
Objective To assess the effect of provision of free glasses on academic performance in rural Chinese children with myopia.
Design Cluster randomized, investigator masked, controlled trial.
Setting 252 primary schools in two prefectures in western China, 2012-13.
Participants 3177 of 19 934 children in fourth and fifth grades (mean age 10.5 years) with visual acuity <6/12 in either eye without glasses correctable to >6/12 with glasses. 3052 (96.0%) completed the study.
Interventions Children were randomized by school (84 schools per arm) to one of three interventions at the beginning of the school year: prescription for glasses only (control group), vouchers for free glasses at a local facility, or free glasses provided in class.
Main outcome measures Spectacle wear at endline examination and end of year score on a specially designed mathematics test, adjusted for baseline score and expressed in standard deviations.
Results Among 3177 eligible children, 1036 (32.6%) were randomized to control, 988 (31.1%) to vouchers, and 1153 (36.3%) to free glasses in class. All eligible children would benefit from glasses, but only 15% wore them at baseline. At closeout glasses wear was 41% (observed) and 68% (self reported) in the free glasses group, and 26% (observed) and 37% (self reported) in the controls. Effect on test score was 0.11 SD (95% confidence interval 0.01 to 0.21) when the free glasses group was compared with the control group. The adjusted effect of providing free glasses (0.10, 0.002 to 0.19) was greater than parental education (0.03, −0.04 to 0.09) or family wealth (0.01, −0.06 to 0.08). This difference between groups was significant, but was smaller than the prespecified 0.20 SD difference that the study was powered to detect.
Conclusions The provision of free glasses to Chinese children with myopia improves children’s performance on mathematics testing to a statistically significant degree, despite imperfect compliance, although the observed difference between groups was smaller than the study was originally designed to detect. Myopia is common and rarely corrected in this setting.
Trial Registration Current Controlled Trials ISRCTN03252665.
PMCID: PMC4172821  PMID: 25249453
16.  STRengthening Analytical Thinking for Observational Studies: the STRATOS initiative 
Statistics in Medicine  2014;33(30):5413-5432.
The validity and practical utility of observational medical research depends critically on good study design, excellent data quality, appropriate statistical methods and accurate interpretation of results. Statistical methodology has seen substantial development in recent times. Unfortunately, many of these methodological developments are ignored in practice. Consequently, design and analysis of observational studies often exhibit serious weaknesses. The lack of guidance on vital practical issues discourages many applied researchers from using more sophisticated and possibly more appropriate methods when analyzing observational studies. Furthermore, many analyses are conducted by researchers with a relatively weak statistical background and limited experience in using statistical methodology and software. Consequently, even ‘standard’ analyses reported in the medical literature are often flawed, casting doubt on their results and conclusions. An efficient way to help researchers to keep up with recent methodological developments is to develop guidance documents that are spread to the research community at large.
These observations led to the initiation of the strengthening analytical thinking for observational studies (STRATOS) initiative, a large collaboration of experts in many different areas of biostatistical research. The objective of STRATOS is to provide accessible and accurate guidance in the design and analysis of observational studies. The guidance is intended for applied statisticians and other data analysts with varying levels of statistical education, experience and interests.
In this article, we introduce the STRATOS initiative and its main aims, present the need for guidance documents and outline the planned approach and progress so far. We encourage other biostatisticians to become involved.
PMCID: PMC4320765  PMID: 25074480
observational studies; guidance for analysis; level of statistical knowledge

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